Systems and methods for enhancing uptake of therapeutic agent from bloodstream into disease site

ABSTRACT

A method, for enhancing uptake, into a disease site, of therapeutic agent administered to the bloodstream, includes sealing a partial enclosure to the patient at the disease site, administering the therapeutic agent to the bloodstream at a first time, and evacuating air from the partial enclosure to produce a partial vacuum in the partial enclosure at a second time that is after the first time by a first delay. A system, for enhancing uptake, into a disease site, of therapeutic agent administered to the bloodstream, includes a first partial enclosure configured to seal to an exposed surface overlying the disease site, a pump configured to produce a partial vacuum in the first partial enclosure to enhance the uptake of the therapeutic agent, and a control module for controlling delay between delivery of the therapeutic agent to the bloodstream and production of the partial vacuum.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.15/559,901, filed Sep. 20, 2017, which is a 35 U.S.C. § 371 filing ofInternational Application No. PCT/US2016/023251, filed Mar. 18, 20176,which claims the benefit of priority from U.S. Provisional ApplicationSer. No. 62/136,082 filed Mar. 20, 2015. All of the aforementionedapplications are incorporated herein by reference in their entireties.

BACKGROUND

According to a recent statistic, cancer is the cause of one in fourdeaths in the United States. The most prevalent cancer treatment methodsare surgery, radiation, and chemotherapy. Additionally, the use ofmagnetic nanoparticle based hyperthermia treatment as a cancer treatmentis increasing. In such hyperthermia treatment, magnetic nanoparticlesare injected directly into the tumor at multiple different locationswithin the tumor to cover the full tumor volume. Subsequent heating ofthe nanoparticles by an external, alternating magnetic field can producelocal temperatures sufficiently high to have therapeutic effect.Commonly, chemotherapy utilizes drugs infused into the patient'sbloodstream. Frequently, two or more cancer treatment methods are usedin combination.

Cancerous tumors are typically characterized by leaky vessels. As aconsequence of the leaky vessels and impaired lymphatic drainage, aswell as rapid growth, cancerous tumors are often associated withabnormally elevated tissue pressure. This elevated pressure impedesuptake, into the cancerous tumor, of therapeutic agents delivered viathe bloodstream, thus reducing the efficacy of chemotherapy and magneticnanoparticle based hyperthermia treatments. To compensate for thiseffect, a relatively large amount of therapeutic agent delivered must beadministered to the patient, which may result in significant sideeffects. Alternatively, other treatment methods, such as surgery orradiation, must be employed.

SUMMARY

In an embodiment, a method for enhancing uptake of a therapeutic agentfrom the bloodstream of patient into a disease site of the patientincludes applying negative pressure to the disease site to form pressuredifferential favorable for transport of the therapeutic agent from thebloodstream into the disease site.

In an embodiment, a system for enhancing uptake of a therapeutic agentfrom the bloodstream of patient into disease site of the patientincludes a partial enclosure. The partial enclosure has an edgeconfigured to interface with an exposed surface of the patient to sealthe partial enclosure to the exposed surface, wherein the exposedsurface overlies the disease site. The system further includes a pumpfor evacuating air from the partial enclosure to produce a partialvacuum in the partial enclosure, to apply a negative pressure to thedisease site so as to enhance uptake of the therapeutic agent into thedisease site.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a system for enhancing uptake of a therapeutic agentfrom the bloodstream into a disease site, according to an embodiment.

FIG. 2 illustrates the partial enclosure of the system of FIG. 1, andthe effect of the system of FIG. 1 on the patient, in further detail,according to an embodiment.

FIG. 3 illustrates a partial enclosure configured to interface with agenerally convex surface overlying the disease site, according to anembodiment.

FIG. 4 illustrates a partial enclosure configured to interface with agenerally concave surface overlying the disease site, according to anembodiment.

FIG. 5 illustrates a method for enhancing uptake of a therapeutic agentfrom the bloodstream into a disease site, according to an embodiment.

FIG. 6 illustrates another system for enhancing uptake of a therapeuticagent from the bloodstream into a disease site, according to anembodiment.

FIG. 7 illustrates a method for enhancing uptake of a therapeutic agentfrom the bloodstream into a disease site, wherein the therapeutic agentis administered to an artery that is upstream from the disease site,according to an embodiment.

FIG. 8 illustrates exemplary timing of the method of FIG. 7, accordingto an embodiment.

FIG. 9 schematically illustrates a partial enclosure with an integratedport for insertion of one or more sensors into the disease site,according to an embodiment.

FIG. 10 illustrates a method for manipulating and evaluating at leastone property of a disease site to guide the application of negativepressure used to enhance uptake of a therapeutic agent from thebloodstream into the disease site, according to an embodiment.

FIG. 11 illustrates two partial enclosures cooperatively configured toapply a pressure gradient to a disease site, according to an embodiment.

FIG. 12 illustrates a system for enhancing uptake of a therapeutic agentfrom the bloodstream into a disease site and improving distribution ofthe therapeutic agent throughout the disease site, according to anembodiment.

FIG. 13 illustrates a method for applying a pressure gradient to adisease site to improve distribution of a therapeutic agent throughoutthe disease site, according to an embodiment.

FIG. 14 illustrates a method for enhancing uptake of a therapeutic agentfrom the bloodstream into a disease site and improving the distributionof the therapeutic agent throughout the disease site, wherein thetherapeutic agent is administered to an artery that is upstream from thedisease site, according to an embodiment.

DETAILED DESCRIPTION OF THE EMBODIMENTS

FIG. 1 illustrates one exemplary system 100 for enhancing uptake of atherapeutic agent from the bloodstream into a disease site. FIG. 1 showssystem 100 in one exemplary use scenario 190, wherein system 100enhances uptake of a therapeutic agent 110 from the bloodstream of apatient 130 into a disease site 120.

System 100 includes a partial enclosure 140 connected to a vacuum pump150. Partial enclosure 140 is sealed to a surface 135 of patient 130 atdisease site 120. Partial enclosure 140 includes one or more edges 142configured to interface with surface 135 to form a seal. Vacuum pump 150evacuates air from partial enclosure 140 to create a partial vacuum 145within partial enclosure 140. Partial vacuum 145 acts upon surface 135to apply a negative pressure in the tissue of patient 130 near surface135. System 100 thus superimposes this negative pressure on the inherenttissue pressure to create a pressure differential between thebloodstream and the disease site more favorable for uptake oftherapeutic agent 110 into disease site 120, as compared to the pressuredifferential associated with the inherent tissue pressure.

Herein, “pressure differential” refers to the pressure of a disease sitemeasured relative to the pressure of the bloodstream near the diseasesite. A “pressure differential” may be positive, negative, or zero. Alsoherein, “inherent tissue pressure” refers to the pressure of the tissuein the absence of system 100, “negative pressure” refers to a pressurethat is less than the atmospheric pressure, and “partial vacuum” refersto an environment having negative pressure. For example, a negativepressure (or a partial vacuum) may be −20 millimeters mercury (mmHg)gauge pressure. In this document, a pressure indicated in units of mmHgis a gauge pressure indicated relative to atmospheric pressure.

Disease site 120 may be (a) a cancerous tumor, (b) an infected area ofpatient 130 such as an area infected with Staphylococcus aureus, a toeinfected with onychomycosis, (c) a disease site having elevated tissuepressure relative to atmospheric pressure, or (d) another type ofdisease site. Therapeutic agent 110 may be a chemotherapy drug, an agentfor magnetic nanoparticle based hyperthermia treatment, an antifungalagent, an antibacterial agent, an antimicrobial agent, anothertherapeutic agent, or a combination thereof. In the case of hyperthermiatreatment of a tumor, system 100 facilitates delivery of magneticnanoparticles to the full tumor volume via a single injection into thebloodstream of patient 130, as opposed to the multiple injections intothe tumor required conventionally.

Surface 135 is an exposed surface of patient 130, which may be anexternal surface of patient 130 (such as the skin of patient 130), aninternal surface of patient 130 accessed through an orifice of patient130, or a surgically accessed and/or surgically formed surface withinpatient 130.

In one embodiment, system 100 further includes a delivery device 115 foradministering therapeutic agent 110 to the bloodstream of patient 130.Delivery device 115 includes, for example, a syringe and/or a catheter.

In one example of scenario 190, the inherent tissue pressure of diseasesite 120 is elevated relative to the surrounding inherent tissuepressure. Thus, in the absence of system 100, the inherent elevatedpressure of disease site 120 creates a positive pressure differentialbetween disease site 120 and the bloodstream. This positive pressuredifferential impedes transport of therapeutic agent 110 into diseasesite 120. However, system 100 applies a negative pressure to diseasesite 120, which reduces or eliminates the positive pressure differentialto enhance uptake of therapeutic agent 110 into disease site 120, ascompared to when the tissue pressure of disease site 120 is unaltered bysystem 100. With a certain strength of partial vacuum 145, system 100may apply a negative pressure sufficient to form a negative pressuredifferential between disease site 120 and the bloodstream, to furtherenhance uptake of therapeutic agent 110 into disease site 120.

In another example of scenario 190, the inherent tissue pressure ofdisease site 120 is comparable to the surrounding inherent tissuepressure. In this case, system 100 applies a negative pressure todisease site 120 to form a negative pressure differential betweendisease site 120 and the bloodstream. This negative pressuredifferential leads to enhanced uptake of therapeutic agent 110 intodisease site 120, as compared to when the tissue pressure of diseasesite 120 is unaltered by system 100.

Partial enclosure 140 is, in an embodiment, made of rubber, plastic,and/or one or more other materials suitable for sealing partialenclosure 140 onto surface 135. In certain embodiments, partialenclosure 140 includes biocompatible and/or latex-free materials.Partial enclosure 140 is sufficiently air tight that vacuum pump 150 iscapable of producing and maintaining partial vacuum 145.

FIG. 2 illustrates partial enclosure 140 (FIG. 1) and the effect ofsystem 100 on patient 130 in further detail. Partial vacuum 145superimposes a negative pressure 220 on the tissue below surface 135 andnear partial enclosure 140. FIG. 2 depicts negative pressure 220 asequipressure contours 222(1), 222(2), and 222(3). Each equipressurecontour 222 indicates a surface of spatially-constant negative pressure220. Without departing from the scope hereof, equipressure contours 222may have shape and extent different from those shown in FIG. 2.

Partial enclosure 140 is positioned on surface 135 overlying diseasesite 120. Although shown in FIG. 2 as being planar, surface 135 may benon-planar, without departing from the scope hereof. Partial enclosure140 has a characteristic size 230 along surface 135. Characteristic size230 may be on the order of millimeters or on the order of centimeters.Alternatively, characteristic size 230 and partial enclosure 140 may beconfigured to seal to a large portion of patient 130 such as a limb orthe majority of patient 130. For example, edges 142 may form a seal thatsurrounds the nose and/or mouth of patient 130, with partial enclosure140 applying partial vacuum 145 to all other portions of patient 130than a region at the nose and/or mouth of patient 130. Disease site 120has a characteristic size 232 along surface 135. One or both ofcharacteristic sizes 230 and 232 are, for example, a diameter. Diseasesite 120 is located at a characteristic depth 234 relative to surface135. Negative pressure 220 has a characteristic depth 236 into patient130 away from surface 135. Characteristic depth 236 is, for example, thedepth at which negative pressure 220 is 10% of its value at surface 135or 1/e of its value at surface 135. Typically, characteristic depth 236is a function of, at least, characteristic size 230 and the strength ofpartial vacuum 145. In the exemplary configuration shown in FIG. 2,characteristic depth 236 is greater than characteristic depth 234 andthe projection (along direction perpendicular to surface 135) of diseasesite 120 onto surface 135 is within partial enclosure 140 such thatsystem 100 exposes all of disease site 120 to negative pressure 220.Since negative pressure 220 penetrates into the tissue of patient 130,disease site 120 need not be in contact with surface 135. Disease site120 may be spaced from surface 135 by a minimum distance 235. Minimumdistance 235 is, for example, a fraction of a millimeter, on ordermillimeters, or on order centimeters. Alternatively, minimum distance iszero.

In one embodiment, partial enclosure 140 is rigid except for havingflexible sealing edges 142. In this embodiment, the rigid portion ofpartial enclosure 140 may be composed, at least in part, of a polymersuch as polyvinyl chloride (PVC), polyacrylate (Acrylic, PMMA), and/orpolyetheretherketone (PEEK), while flexible sealing edges 142 may becomposed, at least in part, of plasticized PVC and/or silicone.

Without departing from the scope hereof, partial enclosure 140 may beconfigured with characteristic size 230 and partial vacuum 145sufficient only to expose a portion of disease site 120 to negativepressure 220. For example, characteristic size 230 may be smaller thancharacteristic size 232, the projection of disease site 120 onto surface135 may fall at least in part outside partial enclosure 140, and/orcharacteristic depth 234 may be greater than characteristic depth 236.Generally, the greatest enhancement of uptake of therapeutic agent 110into disease site 120 is achieved when characteristic depth 234 is smallrelative to characteristic depth 236.

Normal healthy tissue typically has a tissue pressure in the range from−7 to +8 mmHg. However, a cancerous tumor may have elevated tissuepressure in the range from +7 to +38 mmHg. The blood pressure varieswith location in the body due to pressure loss in the vessels and theeffects of gravity. Typically, the blood pressure at the heart averagesapproximately 100 mmHg but decreases to about 20 mmHg in the capillariesand zero mmHg in the small veins. Therefore, in a case where diseasesite 120 is a cancerous tumor, negative pressure 220 is preferably atleast as negative as −38 mmHg at the location of the tumor. The strengthof partial vacuum 145 required to produce negative pressure 220 in thisrange depends on the characteristic depth 234 of the tumor. In oneexample, system 100 may produce a partial vacuum 145 of around −100 mmHgto apply a negative pressure 220 sufficient to fully counteract theelevated pressure of a cancerous tumor. In another example, partialvacuum 145 is in the range from −10 to −150 mmHg.

FIG. 3 illustrates a partial enclosure 340 configured to interface witha generally convex surface 335 overlying disease site 120. Partialenclosure 340 is an embodiment of partial enclosure 140 (FIG. 1), andsurface 335 is an embodiment of surface 135. The configuration shown inFIG. 3 is an example of the configuration shown in FIG. 2, specificallytailored to cooperate with generally convex surface 335. Partial vacuum145 forms a negative pressure 320 within patient 130 at the location ofdisease site 120. Negative pressure 320 is schematically indicated byequipressure contours 322 conceptually similar to equipressure contours222.

FIG. 4 illustrates a partial enclosure 440 configured to interface witha generally concave surface 435 overlying disease site 120. Partialenclosure 440 is an embodiment of partial enclosure 140 (FIG. 1), andsurface 435 is an embodiment of surface 135. The configuration shown inFIG. 4 is an example of the configuration shown in FIG. 2, specificallytailored to cooperate with generally concave surface 435. Partial vacuum145 forms a negative pressure 420 within patient 130 at the location ofdisease site 120. Negative pressure 420 is schematically indicated byequipressure contours 422 conceptually similar to equipressure contours222.

FIG. 5 illustrates one exemplary method 500 for enhancing uptake of atherapeutic agent from the bloodstream into a disease site. In oneexample, system 100 (FIG. 1) performs method 500 to enhance uptake oftherapeutic agent 110 from the bloodstream of patient 130 into diseasesite 120.

In a step 510, method 500 applies a negative pressure to the diseasesite. In one example of step 510, system 100 applies negative pressure220 (FIG. 2) to disease site 120. Step 510 includes steps 512 and 516.

In step 512, method 500 seals a partial enclosure to the patient at thedisease site or near the disease site. Step 512 may include a step 514of sealing the partial enclosure to an exposed surface overlying thedisease site. In one example, of step 512, implemented with step 514, anoperator or a robotic system seals partial enclosure 140 to surface 135,of patient 130, in a location overlying disease site 120, as shown inFIGS. 1 and 2.

In step 516, method 500 evacuates air from the partial enclosure toproduce a partial vacuum within the partial enclosure. The partialvacuum results in the application of a negative pressure to at least aportion of the disease site. In one example of step 516, an operator ora control system activates vacuum pump 150 to produce partial vacuum145, wherein partial vacuum 145 leads to the creation of negativepressure 220 at disease site 120.

Optionally, method 500 includes a step 502 of administering thetherapeutic agent to the bloodstream of the patient. In one embodiment,step 502 includes a step 504 of administering the therapeutic agent to avein of the patient. In one example of step 504, an operator or arobotic system uses delivery device 115 to inject therapeutic agent 110into a vein of patient 130. In another embodiment, step 502 includes astep 506 of administering the therapeutic agent to an artery of thepatient, wherein the artery is upstream (in terms of bloodflow) from thedisease site. One example of step 506 utilizes a catheter, which is anembodiment of delivery device 115, to administer therapeutic agent 110to an artery of patient 130, wherein the artery is upstream from diseasesite 120. In this example, an operator and/or a robotic system mayinsert and operate the catheter to access such an artery. For example,the operator and/or robotic system may, by utilizing techniques known inthe art, insert the catheter into the femoral artery, the radial artery,or another large artery close to the surface of patient 130 and navigatethe catheter to an artery upstream of disease site 120.

Typically, when administering the therapeutic agent into the vein of thepatient, the therapeutic agent is transported to the heart of thepatient and subsequently, through one or more arteries, to the diseasesite. Consequently, when performing step 504, the therapeutic agent ismixed with the blood carried to the heart by all veins such that, uponreaching the heart, the therapeutic agent is diluted into the entireblood volume of the patient. By contrast, when performing step 506 toadministering agents through an artery, the therapeutic agent isdelivered to the area of the disease site at substantially higherconcentration.

In one example of method 500, the disease site is a tumor and thetherapeutic agent is an enzyme intended to degrade the extra-cellularmatrix of the tumor, such as hyaluronidase or collagenase. Generally,when such agents are taken up into a tumor from the vasculature, theymay degrade the extra-cellular matrix of the tumor, which in turn mayreduce the pressure within the tumor. This is a desirable effect thatmay enhance uptake of a therapeutic agent into the tumor. However, whenthe intra-tumoral pressure is reduced by application of negativepressure in step 510, fewer blood vessels within the tumor willcollapse, and consequently greater amounts of a therapeutic agentinjected at a later time may reach the tumor. In a related embodiment ofmethod 500, step 502 is replaced by a step of injecting the enzymedirectly into the tumor.

Without departing from the scope hereof, step 502 may be replaced by astep of administering the therapeutic agent directly to the diseasesite. For example, magnetic nanoparticles may be injected into one ormore locations within the disease site, and application of negativepressure in step 510 may help disperse the magnetic particles within thedisease site.

Although shown in method 500 as preceding application of negativepressure (step 510), administration of the therapeutic agent to thebloodstream (step 502) may take place before and/or during applicationof the negative pressure (step 510), without departing from the scopehereof. In certain embodiments, administration of the therapeutic agentto the bloodstream (step 502) is performed after sealing the partialenclosure to the patient at the disease site (step 512) and beforeevacuating air from the partial enclosure to produce the partial vacuum(step 516). In such embodiments, the time of initiating step 516 mayadvantageously be such that production of partial vacuum 145, and thusapplication of negative pressure 220, coincides with arrival of thetherapeutic agent to the area of the disease site. This particulartiming may serve to at least partly overcome effects associated withself-limiting tissue pressure: With time, tissue tends to respond to anexternally applied negative pressure (such as negative pressure 220) bycounteracting the externally applied negative pressure to once againraise the tissue pressure. By delaying the performance of step 516 untilthe therapeutic agent arrives to the area of the disease site, optimaltissue pressure is achieved at the same time as optimal concentration ofthe therapeutic agent, such that uptake of the therapeutic agent intothe disease site is optimally enhanced. These embodiments of method 500may initiate step 516 a short period of time before arrival of thetherapeutic agent to the disease site, to account for a delay betweenactivation of the vacuum pump and actually achieving a partial vacuum ofsufficient strength.

In an embodiment, method 500 includes a step 550 of optimizing thepartial enclosure for the exposed surface utilized in step 514. Step 550includes a step 552 of determining the profile of the exposed surface.In one example, step 552 determines whether the exposed surface ismostly planar, convex, concave, or a combination thereof. Step 552 mayalso include determining other constraints that influence the optimalshape or size of the partial enclosure. For example, a smaller partialenclosure may be required for accessing internal surfaces such as nearthe cervix, while a larger partial enclosure may be acceptable and/orpreferable for sealing to a female breast. Step 550 further includes astep 554 of configuring or selecting the partial enclosure in accordancewith the determination(s) made in step 552.

FIG. 6 illustrates one exemplary system 600 for enhancing uptake of atherapeutic agent from the bloodstream into a disease site such asdisease site 120. System 600 is an embodiment of system 100 (FIG. 1) andmay perform method 500 (FIG. 5).

System 600 includes partial enclosure 140 coupled with vacuum pump 150.As discussed in reference to FIGS. 1, 2, 3, and 4, partial enclosure 140seals to surface 135 of patient 130 at or near disease site 120. System600 may include delivery device 115, as discussed in reference to FIG.1.

Optionally, system 600 includes one or more of a control module 610, atiming unit 612 implemented in control module 610, a pump control unit618 implemented in control module 610, a magnetometer 630, one or moresensors 620, a sensor processing unit 614 that processes outputs fromsensor(s) 620 and is implemented in control module 610, and an interface616 implemented in control module 610.

In one embodiment, system 600 includes control module 610 with pumpcontrol unit 618 and timing unit 612. Timing unit 612 is communicativelycoupled with pump control unit 618, and pump control unit 618 iscommunicatively coupled with vacuum pump 150. Optionally, timing unit612 is also communicatively coupled with delivery device 115. Pumpcontrol unit 618 controls operation of vacuum pump 150 to producepartial vacuum 145. Pump control unit 618 may control the on/off-stateof vacuum pump 150 as well as the pumping rate of vacuum pump 150. Viapump control unit 618, timing unit 612 controls the timing of pumping byvacuum pump 150. In one implementation, delivery device 115 is coupledwith timing unit 612, and timing unit 612 activates vacuum pump 150 fora pre-specified duration after the time when delivery device 115 startsadministering therapeutic agent 110 to the bloodstream of patient 130.This implementation may serve to avoid or reduce adverse impact from theself-limiting tissue pressure effect discussed in reference to FIG. 5.Optionally, timing unit 612 controls timing of operation of both vacuumpump 150 and delivery device 115. In one implementation, control module610 includes interface 616, and interface 616 communicates timinginformation to an operator, or an external system, and/or receivestiming information from an operator or an external system. In one suchimplementation, an operator or external system may communicate, viainterface 616 to timing unit 612, a set delay between activation ofdelivery device 115 and activation of vacuum pump 150.

In another embodiment, system 600 includes magnetometer 630communicatively coupled with the bloodstream of patient 130.Magnetometer 630 measures the magnetic field at the location ofmagnetometer 630 and is used in conjunction with a therapeutic agent 110that includes a magnetic substance 650. Magnetometer 630 may include amagnetic field generator 632. In one example, magnetic field generator632 generates a magnetic field and magnetometer 630 senses a change inresponse to this applied magnetic field, wherein the change is caused bythe presence of magnetic substance 650. In one example, therapeuticagent 110 is a magnetic nanoparticle based hyperthermia treatment agentand includes magnetic nanoparticles, an example of magnetic substance650, for magnetically induced heating of disease site 120. In anotherexample, therapeutic agent 110 does not rely on magnetic substance 650for therapeutic effect; rather, magnetic substance 650 is added totherapeutic agent 110 as a reporting agent detectable by magnetometer630. Optionally, magnetometer 630 is communicatively coupled with timingunit 612, such that timing unit 612 may control operation of vacuum pump150 based upon detection of magnetic substance 650 by magnetometer 630.In embodiments of system 600 that include magnetometer 630 and controlmodule 610 with timing unit 612, control module 610 may further includeinterface 616. Interface 616 may (a) output one or both of magneticfield measurements by magnetometer 630 and related timing data to anoperator or an external system, and/or (b) communicate to timing unit612 a set delay between detection of magnetic substance 650 bymagnetometer 630 and activation of vacuum pump 150.

Without departing from the scope hereof, magnetometer 630 may bereplaced by a susceptometer, a magnetic imaging system, a magneticparticle imaging system, or other device capable of detecting a magneticproperty change. Additionally, magnetic substance 630 and magnetometer630 may be replaced by, or work in conjunction with, a fluorescentsubstance and an fluorescence detection device, respectively, whereinthe fluorescence detection device is placed externally to patient 130and optically detects the fluorescent substance, without departing fromthe scope hereof.

In yet another embodiment, system 600 includes one or more sensors 620that are inserted into disease site 120 to measure one or moreproperties of disease site 120. Although FIG. 6 shows up to threesensors 620, system 600 may include any number of sensors 620. In oneexample, sensor(s) 620 include a pressure sensor that measures thetissue pressure at a location within disease site 120. System 600, or anoperator, may utilize measurements made by such a pressure sensor toevaluate if partial vacuum 145 is of a suitable strength and,optionally, adjust operation of vacuum pump 150 to adjust the strengthof partial vacuum 145. In another example, sensor(s) 620 include a bloodperfusion sensor that measures blood perfusion at a location withindisease site 120. System 600, or an operator, may utilize measurementsmade by such a blood perfusion sensor to evaluate if blood flow intodisease site 120 is sufficient to achieve a certain degree ofenhancement of uptake of therapeutic agent 110 into disease site 120. Inone implementation, sensor(s) 620 is communicatively coupled withcontrol module 610, and control module 610 includes a sensor processingunit 614 and interface 616. Sensor processing unit 614 processes outputfrom sensor(s) 620 and communicates results to an operator or anexternal system via interface 616. Optionally, sensor processing unit614 is communicatively coupled with pump control unit 618 such thatsystem 600 may adjust operation of vacuum pump 150 based upon feedbackfrom sensor(s) 620.

In one implementation, control module 610 is implemented with aprocessor and machine-readable instructions encoded in non-transitorymemory. In this implementation, the machine-readable instructions, uponexecution by the processor, perform at least a portion of the functionof control module 610. In one example, the machine-readableinstructions, upon execution by the processor, perform the function oftiming unit 612. In another example, the machine-readable instructions,upon execution by the processor, perform at least a portion of thefunction of sensor processing unit 614.

In certain embodiments, system 600 further includes a pump 660configured to generate a positive pressure 665 within partial enclosure140. Positive pressure 665 acts upon surface 135 to apply a positivepressure in the tissue of patient 130 near surface 135. Herein,“positive pressure” refers to a pressure that is greater than theatmospheric pressure. A positive pressure applied to the tissue ofpatient 130, at or near disease site 120, may induce collapse ofcapillaries within disease site 120 to reduce blood flow away fromdisease site 120 and thereby reduce the flow of therapeutic agent awayfrom disease site 120. Pump 618 may be controlled by pump control unit618, for example according to information received from timing unit 612and/or sensor processing unit 614. Without departing from the scopehereof, pumps 150 and 660 may be implemented as a single pump capable ofgenerating both a positive and a negative pressure within partialenclosure 140. When utilizing partial enclosure 140 to apply a positivepressure, partial enclosure may be held onto patient 130 using, forexample, a strap or a mount that affixes partial enclosure 140 to atable/chair on which patient 130 is located.

Without departing from the scope hereof, one, several, or all of timingunit 612, sensor processing unit 614, pump control unit 618, andinterface 616 may be omitted from system 600 and replaced by a humanoperator.

FIG. 7 illustrates one exemplary method 700 for enhancing uptake of atherapeutic agent from the bloodstream into a disease site, wherein thetherapeutic agent is administered to an artery that is upstream from thedisease site. Benefits of administering the therapeutic agent to anartery upstream from the disease site are discussed in reference to FIG.5. Method 700 is an embodiment of method 500 (FIG. 5) and is, forexample, performed by system 600 (FIG. 6).

In a step 710, method 700 performs step 512 of method 500 to seal apartial enclosure to an exposed surface at or near the disease site, asdiscussed in reference to FIG. 5.

In a step 720, the therapeutic agent is administered to an artery thatis upstream from the disease site, as discussed in reference to step 506of method 500. Step 720 is an embodiment of step 502 implemented withstep 506.

In a step 730, method 700 maintains substantially atmospheric pressureat the exposed surface used to seal the partial enclosure. In oneexample of step 730, pump control unit 618 maintains vacuum pump 150 inits off-state during step 730. Without departing from the scope hereof,the pressure within the partial enclosure may be less than atmosphericpressure during step 730, as long as this pressure is insufficient toinduce the self-limiting tissue pressure effect discussed in referenceto FIG. 5.

In a step 740, method 700 performs step 516 of method 500 to produce apartial vacuum in the partial enclosure, thus applying a negativepressure to the disease site, as discussed in reference to FIG. 5. Step740 is an embodiment of step 516 of method 500. In one example of step740, pump control unit 618 turns on vacuum pump 150. By performing step730 prior to step 740, the self-limiting tissue pressure effect is atleast minimized and possibly avoided. As a result, optimal tissuepressure at the disease site is achieved at the same time as optimalconcentration of the therapeutic agent at the disease site. Withoutdeparting from the scope hereof, method 700 may initiate pumping on thepartial enclosure in step 740 shortly before the therapeutic agentarrives to the disease site, in order to account for any delay betweenstart of pumping and actually achieving the partial vacuum.

Without departing from the scope hereof, step 710 may be performed atany time before step 740, for example during step 730.

In one embodiment, step 730 includes a step 732 of maintaining theatmospheric pressure (or reduced pressure insufficient to induce theself-limiting tissue pressure effect) for a pre-specified duration. Thepre-specified duration is, for example, a pre-calculated propagationtime from (a) the location where the therapeutic agent is administeredto (b) the location of the disease site.

In another embodiment, step 720 includes a step 722 and step 730includes a step 734. In step 722, a reporting agent is administeredtogether with the therapeutic agent. In one example of step 722,delivery device 115 administers magnetic substance 650 together withtherapeutic agent 110. In step 734, the bloodstream is monitored for thearrival of the reporting agent to a certain location. In oneimplementation, the monitored location is at the disease site. In anexample of this implementation, magnetometer 630 is positioned atdisease site 120, and timing unit 612 prompts pump control unit 618 toactivate vacuum pump 150 to perform step 740 upon detection of magneticsubstance 650 at disease site 120. In a similar implementation, themonitored location is slightly upstream of the disease site. In anexample of this implementation, magnetometer 630 is positioned slightlyupstream of disease site 120, and timing unit 612 prompts pump controlunit 618 to activate vacuum pump 150 to achieve a pre-specified partialvacuum 145 upon arrival of magnetic substance 650 at disease site 120.In another implementation, the monitored location is away and upstreamfrom the disease site. In an example of this implementation,magnetometer 630 is positioned away and upstream from disease site 120.After detection of magnetic substance 650 by magnetometer 630, timingunit 612 introduces a pre-specified delay before prompting pump controlunit 618 to activate vacuum pump 150, such that partial enclosure 140achieves a pre-specified partial vacuum 145 upon arrival of magneticsubstance 650 at disease site 120. The pre-specified delay introduced bytiming unit 612 is set to substantially match the propagation timetherapeutic agent 110 to disease site 120 from the bloodstream locationmonitored by magnetometer 630.

In certain embodiments, method 700 further includes a step 750 ofreleasing the partial vacuum from the partial enclosure before returningto step 730 and, subsequently, to step 740. These embodiments of method700 are tailored to enhance uptake of remaining, recirculatedtherapeutic agent into the disease site. After the first pass to thearea of the disease site associated with the first iteration of step740, a portion of the therapeutic agent may be carried by veins to theheart, and recirculated to the area of the disease site. At this secondpass and any subsequent passes, the recirculated therapeutic agent isdiluted into the entire blood volume of the patient, and recirculated byone or more arteries to the area of the disease site. Although the firstpass delivers the therapeutic agent to the area of the disease site atmuch higher concentration than the concentrations achievable withrecirculated therapeutic agent, additional passes with dilutedtherapeutic agent may still have therapeutic effect on the disease site.To enhance uptake of recirculated therapeutic agent at the second pass,step 750 releases the partial vacuum after the first iteration of step740 to avoid or reduce the self-limiting tissue pressure effect. Next,method 700 performs step 730, as discussed for the first pass, beforeperforming a second iteration of step 740 coinciding with the secondpass of the therapeutic agent to the area of the disease site. Method700 may perform iterations of steps 750, 730, and 740 to enhance uptakeof recirculated therapeutic agent to the disease site for two or morepasses after the first pass.

Optionally, a step 702 precedes step 710. In step 702, method 700performs step 550 of method 500 to optimize the partial enclosure forthe exposed surface to which the partial enclosure is sealed.

In an embodiment, method 700 further includes a step 760 of applying apositive pressure to the disease site. This positive pressure may inducecollapse of capillaries within the disease site to reduce blood flowaway from the disease site, so as to improve the retention, within thedisease site, of therapeutic agent taken up by the disease site inpreceding step 740. Step 760 may hereby improve the efficacy of thetherapeutic agent on the disease site. In one example of step 760, pumpcontrol unit 618 turns on pump 660 to generate positive pressure 665within partial enclosure 140. Pump control unit 618 may perform thisoperation according to signals received from timing unit 612. In onesuch scenario, timing unit 612 introduces a pre-specified delay betweenstep 740 and step 760. In another scenario, timing unit 612 performsstep 760 immediately after completion of step 740 such that there isessentially no delay between (a) disease site 120 experiencing anegative pressure to enhance the uptake of therapeutic agent 110 and (b)disease site 120 experiencing a positive pressure to improve theretention of therapeutic agent 110 within disease site 120.

FIG. 8 illustrates exemplary timing of method 700 (FIG. 7). A diagram810 shows exemplary administration of a therapeutic agent to thebloodstream as a function of time 840. In one example, diagram 810 showsadministration of therapeutic agent 110 (FIG. 1) using delivery device115. A diagram 820 shows related exemplary application of negativepressure to the disease site as a function of time 840. In one example,diagram 820 shows application of negative pressure 220 (FIG. 2) todisease site 120 by partial enclosure 140 with partial vacuum 145.

At a time 850, method 700 starts step 720 (see diagram 810). Method 700performs step 720 for a duration 852. Duration 852 is, for example, onthe order of seconds, or a fraction of a second. A delay 854 after time850, step 740 applies negative pressure to the disease site (see diagram820). Delay 854 may be on the order of seconds. For example, for a 30centimeter propagation distance to the disease site from the bloodstreamlocation, to which the therapeutic agent is administered, and an averageflow rate of 10 centimeters/second, delay 854 is 3 seconds. Step 740continues for a duration 856 after delay 854. Duration 856 may beidentical to or similar to duration 852 to apply the negative pressurefor the entire time that the therapeutic agent passes through the areaof the disease site. In embodiments of method 700 tailored to enhanceuptake of a second pass of recirculated therapeutic agent, step 740 maybe repeated at a delay 858 after the first application. Delay 858 issimilar to the time between two successive passes of blood through thearea of the disease site. Optionally, method 700 may include severalsuch repeats temporally spaced by delay 858.

A diagram 830 shows, as a function of time 840, exemplary detection of areporting agent administered together with the therapeutic agent.Diagram 830 is related to diagrams 810 and 820. In one example, diagram830 shows detection of magnetic substance 650 by magnetometer 630,wherein magnetometer 630 is positioned slightly upstream from diseasesite 120. Detection of the reporting agent occurs at a delay 860 aftertime 850 and continues for a duration 866 thereafter. Typically,duration 866 is similar to duration 852. In an embodiment of method 700implementing step 734, step 740 is initiated approximately at delay 860after time 850 to apply the negative pressure a further delay 862 afterdelay 860. Diagram 830 illustrates that detection of the reporting agentmay be used to determine when to terminate step 740. Step 740 mayterminate at a delay 864 after end of duration 866. Delay 864 may besimilar to delay 862. In embodiments of method 700 tailored to enhanceuptake of a subsequent passes of recirculated therapeutic agent,associated subsequent passes of the reporting agent may be detectedafter an additional delay 858 after each preceding pass.

A diagram 870 shows optional application of a positive pressure inoptional step 750. Method 700 may initiate step 750 after step 740 witha delay 872 between the termination of step 740 and the start of step750. Delay 872 may be zero, a fraction of a second, in the range fromone to a few seconds, or in the range up to many minutes. Method 700 mayperform step 750 for a duration 874. Duration 874 may be on orderseconds, fractions of a second, about a minute, several minutes, or manyminutes.

Although not shown in diagrams 820 and 830, second and subsequent passesof the therapeutic agent may be temporally broadened. Such broadening isdue to different sub-volumes of the patient's blood traveling todifferent areas of the patient and thus experiencing differentrecirculation times.

Referring now to FIGS. 7 and 8 in combination, method 700 with timing asshown in FIG. 8 may be extended to administration of the therapeuticagent into a vein of the patient, without departing from the scopehereof. If using a vein, the therapeutic agent is diluted into theentire blood volume of the patient also in the first pass.

FIG. 9 schematically illustrates one exemplary partial enclosure 900with an integrated port 910 for insertion of one or more sensors 620(FIG. 6) into disease site 120 (FIG. 1). Partial enclosure 900 is anembodiment of partial enclosure 140, which enables integration ofsensor(s) 620 into the partial enclosure, while being capable ofmaintaining partial vacuum 145 (and/or positive pressure 665) whensealed against patient 130.

Integrated port 910 is configured to penetrate surface 135 and extendinto the tissue of patient 130 to disease site 120 or a location neardisease site 120. Hence, in operation, a portion 920 of integrated port910 penetrates surface 135. At least portion 920, and in certainembodiments more or all of integrated port 910, is needle-shaped.Portion 920 may be a straight or tapered needle. Portion 920 has anaverage outer diameter 925. Average outer diameter 925 may be in therange from 0.1 to 5 millimeters. In one example, average outer diameter925 is in the range from 0.3 to 2.5 millimeters. In another example,average outer diameter 925 is in the range from 0.3 to 1 millimeter.

In certain embodiments, one or more sensors 620 are integrated intointegrated port 910. In one such embodiment, a pressure sensor (such asa Mikro-Tip® Pressure Catheter by Millar, Inc.) is integrated intopartial enclosure 900 to form at least portion 920 of integrated port910. In another such embodiment, a blood perfusion sensor (such as bloodflow probe MNP100NX, MNP100NX-3/10, MNP110NX, MNP150NX, or NX-BF/F, allby Oxford Optronix) is integrated into partial enclosure 900 to form atleast portion 920 of integrated port 910. In an alternate embodiment,integrated port 910 and portion 920 are configured to accept one or moresensor(s) 620.

In one implementation, partial enclosure 900 includes a flexible portion930 that allows a range of orientations of integrated port 910. Theimplementation at least partly decouples the positioning of portion 920from the overall positioning of partial enclosure 900 on surface 135, toaccommodate a variety of possible locations of disease site 120 relativeto surface 135 and partial enclosure 900.

Although not shown in FIG. 9, partial enclosure 900 may include severalintegrated ports 910, without departing from the scope hereof.Furthermore, one or more integrated ports 910 may be used to placemagnetometer 650, a susceptometer, and/or an optical fluorescencedetector (as discussed in reference to FIG. 6) in disease site 120 ornear disease site 120, without departing from the scope hereof. Forexample, a fiber-based optical fluorescence detector having diameter of0.5 or up to 1.0 millimeters may be inserted into patient 130 viaintegrated port 910.

FIG. 10 illustrates one exemplary method 1000 for manipulating andevaluating at least one property of a disease site to guide theapplication of negative pressure used to enhance uptake of a therapeuticagent from the bloodstream into the disease site. Method 1000 may beimplemented into step 516 of method 500 (FIG. 5) and may be performed bysystem 600 (FIG. 6).

In a step 1010, method 1000 inserts at least one sensor into the diseasesite. Each sensor is configured to measure a property of the diseasesite, such as blood perfusion and/or tissue pressure. In one example ofstep 1010, one or more sensors 620 are inserted into integrated port 910of partial enclosure 900 (FIG. 9) and directed to disease site 120. Inanother example of step 1010, one or more sensors 620 are integratedinto partial enclosure 900, as discussed in reference to FIG. 9, andinserted into disease site 120 when partial enclosure 900 is placed onsurface 135.

In a step 1020, method 1000 uses the at least one sensor inserted intothe disease site in step 1010 to measure at least one property of thedisease site, such as tissue pressure and/or blood perfusion. In oneexample of step 1020, one or more sensors 620 integrated into partialenclosure 900, or inserted through integrated port 910 of partialenclosure 900, measures at least one property of disease site 120.Properties measured by sensor(s) 620 may include tissue pressure and/orblood perfusion.

In a step 1030, method 1000 adjusts or maintains the partial vacuumwithin the partial enclosure based upon measurements made in step 1020.Thus, step 1030 adjusts or maintains the negative pressure applied bythe partial vacuum in the partial enclosure. In one example of step1030, sensor processing unit 614 evaluates one or more measurements bysensor(s) 620. Based upon such measurements, sensor processing unit 614may prompt pump control unit 618 to adjust operation of vacuum pump 150to increase or decrease the strength of partial vacuum 145. If sensor(s)620 measures a tissue pressure higher (or lower) than a pre-specifiedvalue, sensor processing unit 614 may send a signal to pump control unit618 that leads pump control unit 618 to increase (or decrease) thepumping rate of vacuum pump 150. If sensor(s) 620 measures a bloodperfusion rate lower (or higher) than a pre-specified value, sensorprocessing unit 614 may send a signal to pump control unit 618 promptingpump control unit 618 to increase (or decrease) the pumping rate ofvacuum pump 150.

Optionally, method 1000 performs steps 1020 and 1030 in an activefeedback loop.

Without departing from the scope hereof, method 1000 may be modified toadjust/maintain a positive pressure in the disease site applied by apositive pressure within the partial enclosure in step 1030. Thismodified embodiment of method 1000 may be implemented in step 750 ofmethod 700.

FIG. 11 illustrates two exemplary partial enclosures 140 cooperativelyconfigured to apply a pressure gradient to disease site 120. Eachpartial enclosure is capable of maintaining a pressure 1145 within thepartial enclosure, which is different from atmospheric pressure. In afirst exemplary scenario, pressure 1145(1) within partial enclosure140(1) is a negative pressure, and pressure 1145(2) within partialenclosure 140(2) is a positive pressure. In this scenario, disease site120 experiences a pressure gradient with increasing pressure in thedirection from partial enclosure 140(1) to partial enclosure 140(2). Ina second exemplary scenario, pressure 1145(1) within partial enclosure140(1) is a positive pressure, and pressure 1145(2) within partialenclosure 140(2) is a negative pressure. In this scenario, disease site120 experiences a pressure gradient with increasing pressure in thedirection from partial enclosure 140(2) to partial enclosure 140(1). Inyet another exemplary scenario, pressures 1145(1) and 1145(2) switch oneor more times between the first exemplary scenario and the secondexemplary scenario to move around, within disease site 120, atherapeutic agent taken up by disease site 120, so as to improve thedistribution of the therapeutic agent throughout disease site 120.

FIG. 12 illustrates one exemplary system 1200 for enhancing uptake of atherapeutic agent from the bloodstream into a disease site, such asdisease site 120, and improving distribution of the therapeutic agentthroughout the disease site. System 1200 is an embodiment of system 100(FIG. 1) and is similar to system 600 (FIG. 6).

As compared to system 600, partial enclosure 140 and vacuum pump 150 arereplaced by two partial enclosures 140 and two pumps 1250. Each pump1250 is coupled to a respective partial enclosure 140 to maintainpressure 1145 therein. As a result, system 1200 is capable of applying apressure gradient to disease site 120, as discussed above in referenceto FIG. 11. Each of pumps 1250 may be controlled by pump control unit618, for example according to information received from timing unit 612and/or sensor processing unit 614.

System 1200 is also capable of applying a negative pressure to diseasesite 120, for example by activating only one pump 1250 to produce anegative pressure 1145 within one partial enclosure 140, or byactivating both pumps 1250 to produce a negative pressure 1145 in bothpartial enclosures 140. In addition, system 1200 is capable of applyinga positive pressure to disease site 120, for example by activating onlyone pump 1250 to produce a positive pressure 1145 within one partialenclosure 140, or by activating both pumps 1250 to produce a positivepressure 1145 in both partial enclosure 140. System 1200 is thus capableof performing method each of method 500 and 700.

In one embodiment, each pump 1250 is capable of producing both apositive pressure and a negative pressure in a partial enclosure 140coupled thereto. In another embodiment, system 1200 may be configuredwith an air handling system that allows for connection of each pump 1250to either one of partial enclosure 140. In this case, one pump 1250 maybe configured for application of negative pressure while the other pump1250 is configured for application of positive pressure. The pressuregradient across disease site 120 may be reversed by switching which pump1250 is coupled with which partial enclosure 140.

FIG. 13 illustrates one exemplary method 1300 for applying a pressuregradient to a disease site, such as disease site 120, to improvedistribution of a therapeutic agent throughout the disease site. Method1300 is similar to method 500, except that step 510 is replaced by astep 1310. Method 1300 may be performed by system 1200, for example withpartial enclosures 140 configured as shown in FIG. 11.

Step 1310 applies a pressure gradient to the disease site. In oneexample of step 1310, system 1200 applies a pressure gradient to diseasesite 120. Step 1310 includes steps 1312 and 1316. Step 1312 seals twopartial enclosures to the patient at or near the disease site.Optionally, step 1312 includes a step 1314 of sealing the partialenclosures to an exposed surface overlying the disease site, asdiscussed above for step 514 in reference to FIG. 5. In one example ofstep 1312, both partial enclosures 140 of system 1200 are sealed tosurface 135 of patient 130 at or near disease site 120. Step 1316applies (a) positive pressure to the tissue of the patient using onepartial enclosure and (b) negative pressure to the tissue of the patientusing the other partial enclosure. In one example of step 1316, pump1250(1) is activated to produce a positive pressure 1145(1) in partialenclosure 140(1), and pump 1250(2) is activated to produce a negativepressure 1145(2) in partial enclosure 140(2),

Optionally, method 1300 includes a step 1320 of repeatedly reversing thedirection of the pressure gradient produced in step 1310. In one exampleof step 1320, the operation of pump 1250(1) is repeatedly changed toproduce a negative pressure 1145(1) in partial enclosure 140(1) insynchrony with the operation of pump 1250(2) being repeatedly changed toproduce a positive pressure 1145(2) in partial enclosure 140(2). Inanother example of step 1320, pump 1250(1) is repeatedly uncoupled frompartial enclosure 140(1) and instead coupled with partial enclosure140(2) and, in synchrony therewith, pump 1250(2) is repeatedly uncoupledfrom partial enclosure 140(2) and instead coupled with partial enclosure140(1), without changing the mode of operation of pumps 1250 apart froma possible interruption.

FIG. 14 illustrates one exemplary method 1400 for enhancing uptake of atherapeutic agent from the bloodstream into a disease site and improvingthe distribution of the therapeutic agent throughout the disease site,wherein the therapeutic agent is administered to an artery that isupstream from the disease site. Method 1400 is similar to method 700except for further including steps 1410 and 1420 between step 740 andoptional step 760. Method 1400 may be performed by system 1200, forexample with partial enclosures 140 configured as shown in FIG. 11.

Step 1410 performs step 1310 of method 1300 to apply a pressure gradientto the disease site. Step 1420 performs step 1320 of method 1300 torepeatedly reverse the direction of the pressure gradient. Since steps1410 and 1420 are performed after step 740, the improved distribution ofthe therapeutic agent is applied to an amount of therapeutic agentenhanced by the performance of step 740. Optionally, method 1400 furtherperforms step 760 after step 1320 to retain a greater amount of thetherapeutic agent within the disease site.

Combinations of Features

Features described above as well as those claimed below may be combinedin various ways without departing from the scope hereof. For example, itwill be appreciated that aspects of one system or method for enhancinguptake of a therapeutic agent from the bloodstream into a disease site,described herein, may incorporate or swap features of another system ormethod for enhancing uptake of a therapeutic agent from the bloodstreaminto a disease site, described herein. The following examples illustratepossible, non-limiting combinations of embodiments described above. Itshould be clear that many other changes and modifications may be made tothe systems and methods described herein without departing from thespirit and scope of this invention:

(A1) A method for enhancing uptake of a therapeutic agent from thebloodstream of patient into disease site of the patient may includeapplying negative pressure to the disease site to form pressuredifferential favorable for transport of the therapeutic agent from thebloodstream into the disease site.

(A2) In the method denoted as (A1), the disease site may have positivepressure greater than pressure of other adjacent tissue, prior toapplying the negative pressure to the disease site.

(A3) In either or both of the methods denoted as (A1) and (A2), the stepof applying negative pressure may include reducing the pressure of thedisease site such that the pressure of the disease site is less than thepressure of other adjacent tissue.

(A4) In any of the methods denotes as (A1) through (A3), the step ofapplying may include sealing a partial enclosure to the patient at thedisease site, and evacuating air from the partial enclosure to produce apartial vacuum in the partial enclosure.

(A5) In the method denoted as (A4), the step of sealing may includesealing the partial enclosure to an exposed surface of the patient,wherein the exposed surface overlies the disease site.

(A6) In the method denoted as (A5), the disease site may be a non-zerodistance away from the exposed surface.

(A7) In the method denoted as (A6), in the step of sealing, the exposedsurface may be skin of the patient.

(A8) In the method denoted as (A6), in the step of sealing, the exposedsurface may be an internal, surgically-exposed surface of the patient.

(A9) In the method denoted as (A6), in the step of sealing, the exposedsurface being an internal surface of the patient accessible through anorifice of the patient.

(A10) The method denoted as (A6) may further include determining theprofile of the exposed surface, and configuring the partial enclosure tomatch the profile.

(A11) In any of the methods denoted as (A4) through (A10), the partialvacuum may be characterized by a negative pressure of magnitude at leastas great as magnitude of positive pressure within disease site.

(A12) In any of the methods denoted as (A4) through (A11), the partialvacuum may be characterized by a negative pressure at least as negativeas −38 mmHg.

(A13) In any of the methods denoted as (A4) through (A12), the partialvacuum may have magnitude greater than magnitude of positive pressurewithin disease site, to account for distance between partial enclosureand the disease site.

(A14) Any of the methods denoted as (A1) through (A13) may furtherinclude administering the therapeutic agent to the bloodstream.

(A15) In the method denoted as (A14), the step of administering mayinclude administering the therapeutic agent to a vein.

(A16) In the method denoted as (A14), the step of administering mayinclude administering the therapeutic agent to artery upstream of thedisease site.

(A17) In the method denoted as (A16), the step of administering mayinclude accessing the artery using a catheter.

(A18) In any of the methods denoted as (A14) through (A17), the step ofadministering may include starting delivery of the therapeutic agent tothe bloodstream at a first time, and the step of applying may includestarting application of the negative pressure at a second time that isafter the first time and offset from the first time by a first delay.

(A19) In the method denoted as (A18), in the step of applying, the firstdelay may match propagation time of the therapeutic agent from (a)location of delivery of the therapeutic agent to the bloodstream to (b)the disease site.

(A20) Either or both of the methods denoted as (A18) and (A19) mayfurther include monitoring the bloodstream to determine time of arrivalof the therapeutic agent to the disease site, and in the step ofapplying, the second time may be the time of arrival of the therapeuticagent to the disease site.

(A21) In the method denoted as (A20), the step of administering mayinclude administering, together with the therapeutic agent, a reportingagent to the blood stream, and the step of monitoring may includedetecting the reporting agent.

(A22) In the method denoted as (A21), the reporting agent may be amagnetic substance, and the step of monitoring may include measuring atleast one of (a) magnetic field and (b) change in response to appliedmagnetic field.

(A23) In the method denoted as (A22), the step of detecting the magneticsubstance may include monitoring, at bloodstream location upstream ofthe disease site, at least one of (i) magnetic field and (ii) responseto applied magnetic field.

(A24) In either or both of the methods denoted as (A22) and (A23), thestep of detecting the magnetic substance may include monitoring, at thedisease site, at least one of (a) magnetic field and (b) response toapplied magnetic field.

(A25) In the method denoted as (A21), the reporting agent may be afluorescent substance, and the step of monitoring may include monitoringfluorescence.

(A26) Any of the methods denoted as (A1) through (A26) may furtherinclude measuring tissue pressure within the disease site using a sensorinserted into the disease site.

(A27) In the method denoted as (A26), the step of applying may includeadjusting the negative pressure according to the tissue pressuremeasured by the sensor.

(A28) Any of the methods denoted as (A1) through (A27) may furtherinclude measuring blood perfusion within the disease site using sensorinserted into the disease site.

(A29) In the method denoted as (A28), the step of applying may includeadjusting the negative pressure according to the blood perfusionmeasured by the sensor.

(A30) Any of the methods denoted as (A1) through (A29) may furtherinclude, after the step of applying negative pressure, applying positivepressure to the disease site to induce collapse of capillaries of thedisease site, so as to improve retention of the therapeutic agent withinthe disease site.

(A31) Any of the methods denoted as (A1) through (A29) may furtherinclude, after the step of applying negative pressure, applying apressure gradient across the disease site, and repeatedly reversing thepressure gradient to improve distribution of the therapeutic agentthroughout the disease site.

(A32) The method denoted as (A31) may further include, after the step ofrepeatedly reversing, applying positive pressure to the disease site toinduce collapse of capillaries of the disease site, so as to improveretention of the therapeutic agent within the disease site.

(B1) A system for enhancing uptake of therapeutic agent from bloodstreamof patient into disease site of the patient may include (a) a firstpartial enclosure with edge configured to interface with an exposedsurface, of the patient and overlying the disease site, to seal thefirst partial enclosure to the exposed surface.

(B2) In the system denoted as (B1), the first partial enclosure may havesize sufficient to apply the negative pressure to all of the diseasesite.

(B3) Either or both of the systems denoted as (B1) and (B2) may furtherinclude a first pump configured to evacuate air from the first partialenclosure to produce a partial vacuum in the first partial enclosure, toapply a negative pressure to the disease site so as to enhance uptake ofthe therapeutic agent into the disease site.

(B4) The system denoted as (B3) may further include a second pumpconfigured to produce a positive pressure within the partial enclosureto apply a positive pressure to the disease site to improve retention ofthe therapeutic agent by the disease site through capillary collapse.

(B5) The system denoted as (B3) may further include (i) a second partialenclosure with edge configured to interface with the exposed surface toseal the second partial enclosure to the exposed surface and (ii) asecond pump for producing a positive pressure within the second partialenclosure to apply, in cooperation with the negative pressure of thefirst partial enclosure, a pressure gradient to the disease site.

(B6) The system denoted as (B5) may further include and a pump controlunit for controlling the operation of the first pump and the second pumpto repeatedly reverse direction of the pressure gradient, to improvedistribution of the therapeutic agent throughout the disease site.

(B7) Any of the systems denoted as (B1) through (B6) may further includea control module for controlling delay between (a) delivery of thetherapeutic agent to the bloodstream and (b) production of a partialvacuum in the first partial enclosure.

(B8) Any of the systems denoted as (B1) through (B7) may further include(i) a magnetometer for detecting magnetic substance propagating throughbloodstream together with the therapeutic agent, to determine time ofarrival of the therapeutic agent to the disease site, and (ii) a controlmodule for synchronizing first production of the partial vacuum with thearrival.

(B9) Any of the systems denoted as (B1) through (B8) may further includea sensor for measuring property within the disease site, and a needlefor inserting the sensor into the disease site.

(B10) In the system denoted as (B9), the needle may be integrated in thefirst partial enclosure for insertion into the patient inside the firstpartial enclosure.

(B11) In either or both of the systems denoted as (B9) and (B10), thesensor may be a pressure sensor for measuring pressure within thedisease site.

(B12) In either or both of the systems denoted as (B9) and (B10), thesensor may be a blood perfusion sensor for measuring blood perfusionwithin the disease site.

(B13) Any of the systems denoted as (B1) through (B12) may furtherinclude a device for detecting reporting agent propagating throughbloodstream together with the therapeutic agent, to determine time ofarrival of the therapeutic agent to the disease site.

(B14) The system denoted as (B13) may further includes a control modulefor synchronizing first production of the partial vacuum with thearrival.

(B15) In either or both of the systems denoted as (B13) and (B14), thedevice may be configured to detect change in at least one magneticproperty, and the reporting agent may include a magnetic substance.

(B16) In either or both of the systems denoted as (B13) and (B14), thedevice may be an optical fluorescence detector, and the reporting agentmay include a fluorescent substance.

Changes may be made in the above systems and methods without departingfrom the scope hereof. It should thus be noted that the matter containedin the above description and shown in the accompanying drawings shouldbe interpreted as illustrative and not in a limiting sense. Thefollowing claims are intended to cover generic and specific featuresdescribed herein, as well as all statements of the scope of the presentsystem and method, which, as a matter of language, might be said to falltherebetween.

What is claimed is:
 1. A method for enhancing uptake, into a diseasesite of patient, of therapeutic agent administered to bloodstream of thepatient, comprising: sealing a partial enclosure to the patient at thedisease site; administering the therapeutic agent to the bloodstream,said administering including starting delivery of the therapeutic agentto the bloodstream at a first time; and evacuating air from the partialenclosure to produce a partial vacuum in the partial enclosure, therebyapplying negative pressure to the disease site to form pressuredifferential favorable for transport of the therapeutic agent from thebloodstream into the disease site, said evacuating including startingevacuation of the partial enclosure at a second time that is after thefirst time and offset from the first time by a first delay.
 2. Themethod of claim 1, the step of sealing comprising sealing the partialenclosure to an exposed surface of the patient, the exposed surfaceoverlying the disease site, the disease site being a non-zero distanceaway from the exposed surface.
 3. The method of claim 1, the partialvacuum being characterized by a negative pressure of magnitude at leastas great as magnitude of positive pressure within disease site.
 4. Themethod of claim 1, the partial vacuum being characterized by a negativepressure at least as negative as −38 mmHg.
 5. The method of claim 1, thepartial vacuum having magnitude greater than magnitude of positivepressure within disease site, to account for distance between partialenclosure and the disease site.
 6. The method of claim 1, the step ofadministering comprising administering the therapeutic agent to a vein.7. The method of claim 1, the step of administering comprisingadministering the therapeutic agent to artery upstream of the diseasesite.
 8. The method of claim 1, in the step of evacuating, the firstdelay matching propagation time of the therapeutic agent from (a)location of delivery of the therapeutic agent to the bloodstream to (b)the disease site.
 9. The method of claim 1, further comprisingmonitoring the bloodstream to determine time of arrival of thetherapeutic agent to the disease site; and in the step of evacuating,the second time being the time of arrival of the therapeutic agent tothe disease site.
 10. The method of claim 9, the step of administeringcomprising administering, together with the therapeutic agent, areporting agent to the blood stream; and the step of monitoringcomprising detecting the reporting agent.
 11. A system for enhancinguptake, into a disease site of patient, of therapeutic agentadministered to bloodstream of the patient, comprising: a first partialenclosure with edge configured to interface with an exposed surface, ofthe patient and overlying the disease site, to seal the first partialenclosure to the exposed surface; a pump configured to evacuate air fromthe first partial enclosure to produce a partial vacuum in the firstpartial enclosure, to apply a negative pressure to the disease site soas to enhance the uptake of the therapeutic agent; and a control modulefor controlling delay between (a) delivery of the therapeutic agent tothe bloodstream and (b) first production of a partial vacuum in thefirst partial enclosure.
 12. The system of claim 11, the first partialenclosure having size sufficient to apply the negative pressure to allof the disease site.
 13. The system of claim 11, further comprising amagnetometer for detecting magnetic substance propagating throughbloodstream together with the therapeutic agent, to determine time ofarrival of the therapeutic agent to the disease site; and the controlmodule being configured to for synchronizing the first production of thepartial vacuum with the arrival.
 14. The system of claim 11, furthercomprising: a sensor for measuring property within the disease site; anda needle for inserting the sensor into the disease site.
 15. The systemof claim 14, the needle being integrated in the first partial enclosurefor insertion into the patient inside the first partial enclosure. 16.The system of claim 14, the sensor being a pressure sensor for measuringpressure within the disease site.
 17. The system of claim 14, the sensorbeing a blood perfusion sensor for measuring blood perfusion within thedisease site.
 18. The system of claim 11: further comprising a devicefor detecting reporting agent propagating through bloodstream togetherwith the therapeutic agent, to determine time of arrival of thetherapeutic agent to the disease site; and the control module beingconfigured to synchronize the production of the partial vacuum with thearrival.
 19. The system of claim 18, the device being configured todetect change in at least one magnetic property, and the reporting agentincluding a magnetic substance.
 20. The system of claim 18, the devicebeing an optical fluorescence detector, and the reporting agentincluding a fluorescent substance.